We have studied a group (n=23) of HIV-infected individuals termed long- term non-progressors (LTNPs) whose disease has not progressed over periods ranging from 7 to 17 years. Levels of viral burden and virus replication were quite low in peripheral blood (PB) and lymph node (LN) mononuclear cells (MC) of LTNPs compared to progressors. Of interest was the fact that relatively high levels of plasma viremia were noted in the majority of LTNPs, comparable to levels in HIV-infected individuals whose disease had progressed. The degree of follicular hyperplasia and the total nodal and germinal center areas were significantly less in LTNPs. Of note, and in striking contrast to progressors, the lymph node architecture of the LTNPs were preserved despite several years of infection. Variable degrees of virus trapping was detected; several patients had little if any trapping of extracellular virions. Virus particles were virtually never detected in tissue or cell suspensions by electron microscopy. Only rarely were individual cells detected that were expressing HIV. The lack of virus trapping could in part explain the fact that although only very few cells were actively producing virus in LN, plasma viremia seemed not to be efficiently cleared leading to relatively high levels of plasma viremia. These data together with studies of lymphoid tissue in progressors suggests that disease progression is at least in part related to the deposition of virions on the follicular dendritic cell network of LN germinal centers, persistent activation of LN, active virus replication, and progressive destruction of lymphoid tissue. From an immunological standpoint, HIV-specific cytotoxicity against gag proteins was consistently observed in PBMC of LTNPs. Proliferative responses to a variety of stimuli (mitogens, alloantigens, and recall antigens) were preserved in PBMC of LTNPs. Characterization of humoral immune responses is currently underway. Intensive study of LTNPs should shed valuable insight into the pathogenic mechanisms of HIV disease and hopefully will provide important information for the development of therapeutic and vaccine strategies.